Substituted naphthoquinones



Patented July 27, 1943 UNITED" SU STITUTED,Narnrnooumonss Max Tishler,Rahway, N. J .,-'assiguor to Merck & Co. Inc., Rahway, N. 3., acorporation of New. 1

NoDrawing. Original application April 6, 1940,

Serial No. 328,265, now Patent No. 2,306,093, dated December 22, 1942.Divided and this application May 19, 1942, Serial No.,443,641-

"4 Claims. (c1. 2 6- 4529) This isa division of co-pending applicationSerial No. 328,265, filed April 6, 1940, for Substitutednaphthoquinones.

This invention relates to gamma substituted propyl derivatives of1,4-naphthoquinone, inter-;

mediates; and processes for their. production.

Doisy .and'others, J. A. C. S. 61-: 1295, (May,

1939), Jour. Biol. Chem. 130:219, 433 (1939), re-

port experiments in which vitamin K1 hasbeen hydrogenated in thepresence ,-,oi a platinum catalyst in acetic acid according to thefollowing When the hydrogenation product is oxidized, Compound III, 2methyl 3 dihydrophytyl- 5,6,7,8,tetrahydro-1,4-naphthoquinone is formed.,Doisy apparently did not isolate and characterize his reaction product.

Doisys experiments were repeated by me, and their procedure was alsomodified by the use of various other forms of platinum and palladiumcatalysts and various othersolvents. The hydrogenation product wasisolated as the hydroquinone, purified and then oxidized by the usualmethods. The product is a golden yellow liquid which, on reductiveacetylation, yields a crystalline diacetate which may be crystallizedfrom alcohol. In Doisys process after hydrogenation of the quinonegroups, both the benzene rings andthe side chains appear to be reducedsimultaneously when the usual platinum or palladium catalysts are used.The firstmolecule of hydrogen is taken up with extreme rapidity and whenthe reaction-isstopped at this point, the-product,

after exposure to air, is vitaminKi, indicating that the quinone systemis the first to be reduced.

When the reaction is allowed to proceed, hy-

dIOgen is absorbed at an almost constant rate until three more moleculesof hydrogen have been absorbed. That the reduction is not selective isshown by the fact that when. the reaction is stopped after three mols.of hydrogen have been absorbed, appreciable quantities of vitaminK or ofreduction products which still contain a double bond in the side chainare pres; ent. p This isindicated by treating a sample of the reactionimixture with alcoholic alkali wl ere by a transient purple color isformedf This test ischaracteristic of quinones having a substitutedally] group in the two or three position. V

Karrer, Helv. 22:1515 (Dec. 1, 1939) reports the production of a2-methyl-3-dihydrophyty1- 1,4-naphthoquinone by condensing dihydrophytylbromide with 2-methy1-1,4-11apl1thohydroquinone'in the presence of acatalyst. Beyond this, 'he'jgives no details.

I have found that gamma substituted allyl naphthoquinones may beselectively reduced to form gamma substituted propyl naphthoquinones. Inthe case of allylic side chains in which aliphatic alkyl radicals aresubstituted in the gamma position, the selective reduction is preferablycarried out with Raneys nickel as a catalyst in methyl alcohol.Following the absorption of 2 mols. of hydrogen, the reaction proceedsvery slowly. By stopping the reduction at this point, gamma substitutedpropyl naphthoquinones may be obtained in excellentyield. 7

Where an aryl group is substituted in the gamma position of the allylside chain, Raneys nickel does not appear to be a suitably activecatalyst,

and it is necessary to use a catalyst such as pal ladium.,

These gamma substituted propyl naphthoquinones show pronouncedantihemorrhagic activity and are useful as therapeutic agents.

In the examples given below, preferred methods of carrying out myinvention are illustrated, but it is to be understood that they aregiven by way of illustration and not of limitation and thatmodifications may be made by those skilled in the art without departingfrom the spirit and scope of the invention.

EXAMPLE I EXAMPLE II 2-METHYL3(BETA GAMMA DIHYDROPHYTYL)-1,4- 2 (BETAGAMMA DIHYDROPHYTYD4 4 NAPHTHOQUINONE action is stopped and the mixture.filtered; The;

filtrate is diluted with water whereupon a waxy solid separates. Themixture. is extracted with petroleum ether, chilled at. #10910; andcentrii uged. The supernatant liquid is; discarded and the white waxyresidue is washed? three times;

with small portions of cold petroleum ether. The

residue, which is 2-methyl-3-dihydrophytyl-1;4=

naphthohydroquinone,. a. waxy solid melting at 7 about 80 C., isdissolved in ether and shaken with 1 gx. of silver oxide and anhydrousmagnesium sulfate. After minutes; the mixtureis filtered, and theyellowfiltrate concentrated;

'The product is a golden yellow; liquid.

Analysis Carbon Hydrogen Calculated Found'un Unlike vitamin K1 (thestarting material) the-1 product does not give a-tr-ansient purple colorwhen heated with alcoholic alkali. It shows pronounced antihemorrhagicactivity in chicks at doses of G gamma. On reductive acetylation, the

product yields a white solid, the diacetate: of2'-methyl-3-dihydrophytyl-1,4-naphthohydroquinone, melting at about 56C;

. Analysis Carbon Hydrogen- Calculated 78.02 10.09- Found 7 1.02 10.06

NAPHTHOQUINONE A. mixture of; 11 gx. of; 2-phytyl-.-1-,4-naphthoquinone,251 co..v of methanol and 0.25 gx. of Raneys nickel catalyst is shakenwith hydrogen until 102 cc. of hydrogen are absorbed. The mixture isfiltered, the filtrate diluted with water and extracted with 10 cc. ofpetroleum ether. The petroleum ether extract is chilled at 10 C. forone-half hour andthen centrifuged. The white waxy residue, afterwashingwith petroleum ether several times, is.Z-dihydrophytyl-1,4-naphthohydroquinone; which is dissolved in etherand oxidizedjby'shakingwith silver oxide in the presence of'anhydrouszmagnesium sulfate. By concentrating under vacuum, the productis obtained as agolden yellow oil.

Analysis.

l I Carbon Hydrogen in which R is a member of the group consisting ofhydrogen and acetyl, and R is a member of the group consisting ofhydrogen and methyl.

2. 2-methyl-3-dihydrophytyl, .lA-naphthohydroquinone. 1

3. Diacetate of 2-methyl-3-dihydrophytyl-1,4-

' naphthohydroquinone.

4. Z-dihydrophytyl-1,4-naphthohydroquinone.

MAX TISHLER.

